Method of and means for diagnosis of ingested drugs with radio-opaque and other indicators



United States Patent 3 341,417 METHOD OF AND MEANS FOR DIAGNOSIS OF INGESTED DRUGS WITH RADIO-OPAQUE AND OTHER INDICATORS Edwin S. Sinaiko, 5555 S. Everett Ave., Chicago, II]. 60627 No Drawing. Filed July 14, 1965, Ser. No. 472,060 Claims. (Cl. 167-845) This application is a continuation-in-part of my copending application Ser. No. 271,887, filed Apr. 10, 1963, now abandoned.

The present invention relates to a novel method and means for the diagnosis of an ingested drug, especially of the barbiturate type, and more particularly to the utilization of a radio-opaque or other indicator or marker to indicate the amount and type of an ingested drug by means of an X-ray of a patients abdomen or urinalysis.

Posioning by barbiturates often involves death after a long period in a coma unless suitable treatment is performed to revive the patient. Many times treatment must be delayed while laboratory tests are performed to determine if drugs have been taken into the system which would result in a coma. Thus, the need for immediate identification, determination of dosage, and determination of the period of time which has elapsed since ingestion is a very important one in the differential diagnosis of coma due to ingested drugs.

The large number of cases of barbiturate poisoning due to heavy sale of these drugs, with or without prescriptions, has focused attention upon the necessity of identifying the barbiturates and their metabolites. According to known texts on toxicology the methods of identification of the barbiturates are many and slow, and none are completely satisfactory. To successfully identify such compounds, the group must be isolated from the viscera. The common fluids used for analysis to determine if drugs are involved are stomach washes, blood and urine, and the quickest extraction procedures for all these fluids is a direct extraction using ether of chloroform as the organic solvent.

However, each of these fluids have disadvantages in their analysis. For example, considerable quantities of the barbiturates are lost in the formation of water soluble salts. Such loss also depends on the pH of the solution in the stomach. In blood tests, chromagenes interfere with the identification of assay and, therefore, the chromagenes must be extracted with chloroform. In the urine, the metabolites of barbiturates are also present and identification is difficult because the extract crystallizes and these crystals are not specific.

Polymorphic forms of many barbiturates exist, and X-ray defraction techniques are utilized for identification, and also different solvent techniques and micro melting points are useful. A more recent technique is the purification using chromatography and counter-current techniques followed by identification. Other routine methods of analysis are X-ray diffraction, infra-red spectrophotometry and assay by means of ultra-violet spectrophotometry. However, all of these analysis techniques require considerable time for proper determination and, in the meantime, valuable time is lost before proper treatment may be prescribed.

An important object of the present invention is the provision of a novel indicator to aid in the differential diagnosis of coma. More specifically, this invention relates to a novel method and means to definitely diagnose the 3,341,417 Patented Sept. 12, 1967 cause of coma as due to ingested drugs through a quick and simple test which is easily performed on the patient in coma, without the attendant disadvantages found in prior diagnostic procedures.

Another important object of the present invention is the provision of a method for determining the type of an ingested drug, the amount of the ingested drug and the approximate time elapsed since ingestion. This method involves the addition to the dosage units of the drug marketed for oral ingestion of a non-toxic, relatively insoluble radio-opaque substance which will be visible upon the taking of an X-ray of the patients abdomen. By observing the shape or configuration of the radioopaque substance, the number or amount of the substance and the position or location of the substance in the gastrointestinal tract, one can readily diagnose these three variables cited above.

The present invention further comprehends the provision of a relatively insoluble radio-opaque marker or indicator which may be incorporated in a dosage unit of the drug marketed for oral ingestion with the indicator of a distinct shape or design which may be quickly determined and disclosed by X-ray. Thus, various drugs may be identified by a distinctively shaped marker in the dosage unit of that drug. Further, knowing the marker utilized in a certain dosage unit such as tablet, pill or capsule, one may diagnose the quantity of the drug taken by the number of markers in the patients abdomen or intestinal tract.

The present invention also comprehends the provision of a relatively insoluble radio-opaque marker or indicator incorporated in a gelatin capsule containing the drug to be ingested. The radio-opaque marker is barium sulfate which is incorporated in the gelatin capsule by mixing a liquid suspension of barium sulfate and a gelatin solution and forming the gelatin capsule with the barium sulfate incorporated therein in a conventional manner.

The present invention also comprehends the provision of an indicator incorporated into a dosage unit which will appear in the urine of the patient, such as methylene blue and certain other azo dyes of different distinctive colors. Thus, the urine of a patient in coma would exhibit the distinctive dye substance.

Further objects and advantages of my invention should be apparent to those skilledin the art from the following description.

This invention relates to differential diagnosis of coma and more particularly to whether coma was induced due to ingested drugs. A doctor is frequently called in to see a patient in coma. The differential diagnosis of coma is o ten difiicult because of the various numerous conditions which might cause it, and causes must be ruled out one by one before definitive treatment can be instituted.

Since barbiturate poisoning is not an uncommon 0ccurrence, an immediate method of determining its ingestion would considerably shorten the time required for diagnosis. The present invention concerns the incorporation into each dosage unit of the drug a non-toxic, relatively insoluble indicator such as a radio-opaque marker providing a distinctive shape or configuration which would be ingested simultaneously with the drug. A patient in coma could then have an ordinary X-ray (fiat plate) of the abdomen and the marker would show up on the X-ray plate to indicate the type of drug, quantity and dosage that had been ingested, and treatment could be immediately instituted.

Barbiturates are normally divided into three chemical groups having varying times of duration of effectiveness:

The R-l,5,5 group are long duration compounds, the R-5,5 group are of intermediate duration and the thiobarbiturates are of relatively short duration. Most of these compounds are in the sodium salt form at the number 1 position on the ring as follows:

Pentothal sodium is a thiobarbiturate with R-ethyl and R'CHaCH2CHzCH.

Another well known barbiturate is phenobarbital which is in the R-5,5' group with R-ethyl and R'-phenyl. Although there are three groupings for the barbiturates, their treatment is substantially identical. Treatment involves the persistent administration of central nervous system stimulants (stimulant analeptics), such as picrotoxin, pentylene-tetrazol, nikethamide or bemegride, various supportive procedures, and artificial respiration or oxygen if necessary.

Since treatment for barbiturate poisoning is generally the same for all types of barbiturates, the problems are resolved to the dosage and the time when the drug was ingested. Although the effect of barbiturates in toxic doses on the mobility of the gastrointestinal tract is to slow it and produce stasis, knowing where the drug lies spatially in the tract may be an important advantage in treating the patient. The location of the radio-opaque indicator in the X-ray plate would give a clue as to where in the intestine the drugs (if not completely absorbed) were, and some indication in the time needed to reach that level; therefore, the approximate time when the drug was taken.

Now referring specifically to the radio-opaque indicators which are contemplated for use in the dosage units marketed for oral ingestion. One such indicator is a treated insoluble cord or thread which is radio-opaque, which may be incorporated in a standard size gelatin capsule. Dosages of drugs such as barbiturates are generally standardized quantities. Thus, adding a small section of a cord of a radio-opaque material to the contents of each unit having a known dosage will indicate that drug and quantity if shown on an X-ray plate. If there are several different dosage quantities for the drug, the radio-opaque cord marker will be distinctive for each dosage level. For example, one dosage quantity would have a straight cord in the unit or capsule, a different dosage would have a cord knotted at short intervals, a third dosage could have a cord which has a coiled configuration and a fourth dosage could be a complete circle of the radio-opaque material. Such a cord is formed of polyvinyl chloride and barium sulfate; the barium sulfate being a commonly used radio-opaque material.

Another type of marker which may be incorporated in a dosage unit of the drug marketed for oral ingestion would be a small ball of stainless steel or like material which would be unaifected by the stomach acids or other fluids in the body and which would be nontoxic so as not to be injurious to the health of the person. To differentiate between different dosage levels, the stainless steel member may take a number of shapes which would be easily recognizable upon an X-ray plate, such as a sphere or ball, a square or polygonal shape, an ellipsoid, a star, etc.

A third type of radio-opaque marker or indicator is the utilization of barium sulfate incorporated in the capsule body holding the drug to be ingested. A liquid suspension of barium sulfate and gelatin in water is mixed together and gelatin capsules are formed with the barium sulfate incorporated in the gelatin capsule wall; the capsules being formed in a conventional manner. The capsules will show up on an X-ray plate in the distinctive shape of the capsule due to the barium sulfate, and the barium sulfate will still be clearly seen on an X-ray even where the capsule has completely dissolved.

The distinctive marker could also be formed of a radio-opaque plastic of a distinctive shape or configuration, either two or three dimensional, which may be incorporated in the drug in the pill or capsule, or the plastic marker may be incorporated in the wall of the gelatin capsule. Also, rather than the use of barium sulfate, a radio-opaque ink may be utilized to provide a distinctive marking on the wall of the capsule.

A fourth type of radio-opaque marker involves the use of a radio-opaque plastic which is extruded into a hollow tube having a distinctive cross section. Such a radio-opaque plastic would be a polyvinyl chloride plastic impregnated with barium sulfate. The hollow interior of the extruded tubing may have a variety of distinctive shapes or peripheries only limited by the complexity of the extrusion die. The barbiturate or other medicine is inserted into the hollow tubing as a powder or in a suspension and solidified to provide a solid core in the tube. Then the tubing is sliced transversely to provide the individual dosage unit and coated with an ultimate candy coating that dissolves in the stomach. The plastic tubing will not dissolve and thus will show up on an X-ray plate. Such a plastic would not be toxic to the individual.

Although the description of this invention has dealt primary with barbiturate poisoning which is presently the most common source of poisoning producing coma, this concept of radio-opaque markers may be advantageously applied to other drugs which may produce coma or whenever or wherever it would be deemed expedient for medical intelligence to determine objectively time of ingestion and dosage. The varying configurations of the markers could differentiate between drugs as well as differentiating between dosage levels.

Another type of indicator which may be incorporated in a solid dosage unit of a drug marketed for oral ingestion would be the use of certain azo dyes of different colors, such as methylene blue, which would appear in the urine of the patient. Although the patient is in a comatose condition, the patient would be catheterized and the urine removed would exhibit the dye substance found in the drug. Various types of drugs capable of causing coma would contain various easily identifiable azo dye colors, and this indicator would not be limited to solid dosage units but could also be incorporated in liquids, solutions or elixirs.

By the use of the markers in the drugs to be ingested or in the body of the capsule or pill, a doctor can tell by the number, configuration and location of a marker on an X-ray plate the type of drug, the dosage and number of dosage units ingested, and the approximate time of ingestion. These factors will determine the treatment to be followed and the degree of intensity of treatment.

In the foregoing description, the drugs are generally identified as dosage units marketed for oral ingestion and it is intended such shall include capsules, pills or tablets incorporating the drug therein in a standard dosage used for treatment purposes.

Having thus disclosed the invention, I claim:

1. A method of determining durg poisoning by in vivo roentgenographic identification of ingested peroral dosage units of drugs in a comatose subject, which comprises roentgenographing the gastro-intestinal tract of a comatose subject who has previously ingested peroral dosage units, each containing therein a specific amount and type of drug and a distinctively shaped radiopaque marker identifying that specific amount and type of drug, in order to thereby identify such markers present.

2 A method of determining drug poisoning as set forth in claim 1, in which the number of radiopaque markers indicated on the roentgenograph indicates the number of dosage units ingested and their position in the gastro-intestinal tract indicates the approximate time of ingestion.

3. A method of determining drug poisoning by in vivo roentgenographic identification of ingested peroral dosage units of drugs in a comatose subject, which comprises roentgenographing the gastro-intestinal tract of a comatose subject who has previously ingested peroral capsules, each containing therein a specific amount and type of drug and a specific type of distinctively configured radiopaque material incorporated in the capsule wall identifying that specific amount and type of drug, in order to thereby identify such markers present.

4. A method of determining drug poisoning by in vivo roentgenographic identification of ingested peroral dosage units of drugs in a comatos subject, which comprises roentgenographing the gastro-intestinal tract of a comatose subject who has previously ingested peroral capsules, each containing therein a specific amount and type of drug and a specific type of distinctive confiugred shaped radiopaque marker identifying that specific amount and type of drug, in order to thereby identify such markers present.

5. A method of determining drug poisoning as set forth in claim 4, in which the radiopaque marker is distinctively shaped to indicate the dosage level of the drug.

6. A method of determining barbiturate poisoning by in vivo roentgenographic identification of ingested peroral dosage units of barbiturate drugs in a comatose subject, which comprises roentgenographing the gastrointestinal tract of a comatose subject who has previously ingested peroral dosage units, each containing therein a specific amount and type of barbiturate drug and a specific type of distinctively configured shaped radiopaque marker identifying that specific amount and type of barbiturate drug, in order to thereby identify such markers present.

7. A method of determining barbiturate poisoning by in vivo roentgenographic identification of ingested peroral dosage units of barbiturate drugs in a comatose subject, which comprises roentgenographing the gastrointestinal tract of a comatose subject who has previously ingested peroral dosage units, each containing therein a specific amount and type of barbiturate drug and a specific type of distinctively configured shaped radiopaque marker embedded therein identifying that specific amount and type of barbiturate drug, in order to thereby identify such markers present.

8. A method of determining barbiturate poisoning as set forth in claim 7, in which varying dosages of the barbiturate drug are indicated by different configurations of said marker, and the number and position of the markers indicate the number of dosage units ingested and the approximate time of ingestion.

9. A method of determining drug poisoning by identification of azo dye in the urine of a comatose subject, which comprises catheterizing urine from a comatoes subject who has previously ingested peroral dosage units, each containing therein a specific amount and type of drug and a specific type of azo dye distinctively identifying that specific amount and type of drug, in order to thereby identify the type of azo dye present.

10. A method of determining barbiturate poisoning by identification of azo dye in the urine of a comatose subject, which comprises catheterizing urine from a comatose subject who has previously ingested peroral dosage units, each containing therein a specific amount and type of barbiturate drug and a specific type of azo dye distinctively identifying that specific amount and type of barbiturate drug, in order to thereby identfy the type of azo dye present.

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LEWIS GOTTS, Primary Examiner. S. K. ROSE, Assistant Examiner.

A. (Sci. Ed.) 43, 357 to (5020), 45 to 47, Jan. 16,

Am. J. Vet. Res. 20, 977 to 984,

A. (Sci. Ed.) 34, to 138 

1. A METHOD OF DETERMINING DURG POISONING BY IN VIVO ROENTGENOGRAPHIC IDENTIFICATION OF INGESTED PERORAL DOSAGE UNITS OF DRUGS IN A COMATOSE SUBJECT, WHICH OMCPRISES ROENTGENOGRAPHING THE GASTRO-INTESTINAL TRACT OF A COMATOSE SUBJECT WHO HAS PREVIOUSLY INGESTED PERORAL DOSAGE UNITS, EACH CONTAINING THEREIN A SPECIFIC AMOUNT AND TYPE OF DRUG AND A DISTINCTIVELY SHAPED RADIOPAQUE MARKER IDENTIFYING THAT SPECIFIC AMOUNT AND TYPE OF DRUG, IN ORDER TO THEREBY IDENTIFY SUCH MARKERS PRESENT. 